Acute kidney injury is common amongst hospitalized and critically ill patients and its incidence is increasing. Approximately 45% of critically ill patients and 20% of hospitalized patients develop acute kidney injury (Li P K et al. Kidney Int. 2013; 83:372; Bellomo R, et al. Lancet 2012; 380:756-766; Goldstein S L Blood Purif. 2012; 33:131-137). The result is increased hospital stays, infectious complications and increased mortality at significant cost (Nash H et al. Am J Kidney Dis. 2002; 39:930; Liangos O et al. Clin J Am Soc Nephrol. 2006; 1:43; Xue J L et al. J Am Soc Nephrol 2006; 17:1135; Palevsky P M N Engl J Med. 2009; 361:1699; Himmelfarb J and Ikizler T A Kidney Int 2007; 71:971; Schrier R W et al. J Clin Invest. 2004; 114:5; Singbartl K et al. Kidney Int 2012; 81:819-825). Recent studies have also linked episodes of acute kidney injury with future development of chronic kidney disease (Coca S G et al. Kidney Int. 2012; 81:442; Bydash J R et al. Clin J Am Soc Nephrol. 2011; 6:2555). Multiple factors contribute to the development of acute kidney injury including sepsis, ischemia, drugs, intravenous contrast, and infection (Star R A Kidney Int 1998; 54:1817; Thadhani R et al. N Engl J Med 1996; 334:1448; Perazella M A Kidney Int. 2012; 81:1172-1178; Zarjou A and Agarwal A J Am Soc Nephrol. 2011; 22:999; Solomon R and Dauerman H L Circulation 2010; 122:2451; Collins A J et al. Am J Kidney Dis. 2011; 57(1)(suppl 1):e1-e526).
The current standard for identifying acute kidney injury, serum creatinine, is non-specific and insensitive (Waikar S S, et al. 2009; 24:3263; Bolignano D. Clin Chem Lab Med 2012; 50:1495; Star R A. Kidney Int. 1998; 54:1817). Serum creatinine may not increase until days after the injury has occurred or until 50% of renal function has been lost, precluding effective treatment. Additionally, conditions other than kidney injury may cause elevations in serum creatinine. Moreover, serum creatinine is unable to accurately predict glomerular filtration rate (GFR) in the non-steady state of acute kidney injury, underestimating the decline in renal function. Lastly, since serum creatinine depends on muscle mass and hepatic function, serum concentrations may differ depending on the patient's muscle content and liver function (Waikar S S, et al. Nephrol Dial Transplant 2009; 24:3263; Bolignano D. Clin Chem Lab Med 2012; 50:1495; Star R A. Kidney Int. 1998; 54:1817).
There is a critical unmet need for a real-time, specific, and sensitive biomarker of acute kidney injury. The American Society of Nephrology, Acute Dialysis Quality Initiative, and Acute Kidney Injury Network have all prioritized the identification and validation of acute kidney injury biomarkers (Kellum J A et al. Clin J Am Soc Nephrol. 2008; 3:887; Mehta R L et al. Crit Care 2007; 11:R31). Early detection of acute kidney injury may allow for timely intervention and perhaps decrease its significant morbidity and mortality (Schrier R W J Am Soc Nephrol 2004; 15:2756). Although multiple new drugs have been developed to treat acute kidney injury, they have not proven effective in a clinical setting (Noguchi S, et al. J Pharmacol Exp Ther 1993; 267:919-26; Conger J D, et al. Kidney Int 1989; 35:1126-32; Allgren R L, et al. N Engl J Med. 1997; 336:828-34; Tumlin J A, et al. Am J Kidney Dis 2005; 46:26-34; Hirschberg R, et al. Kidney Int. 1999; 55:2423-32; Denton M D, et al. Kidney Int. 1996; 50:4-14; Acker C G et al. Kidney Int. 2000; 57:293-8). This has been attributed, at least partially, to the inability to detect kidney injury early. Multiple studies have investigated a variety of plasma and urine biomarkers for the diagnosis of acute kidney injury (Kashani K et al. Crit Care 2013; 17:R25; Siew E D et al. J Am Soc Nephrol. 2011; 22:810; Dieterle F, et al. Nat Biotechnol. 2010; 28:455; Devarajan P Nephrology (Carlton) 2010 15:419; Waikar S S and Bonventre J V Nephron Clin Pract 2008; 109:c192). Although significant progress has been made, no specific, early biomarkers of acute kidney injury have translated into clinical practice.